The immune cell we have cloned has a classical two-chain T-cell receptor (TCR), but is not restricted by the Major Histocompatability Locus (MHC). It can recognize 10 of 11 human renal cancers tested, despite their not sharing any of the (MHC) molecules normally needed for immune recognition. This T-cell clone does not react with B-cell lines, normal fibroblasts or other T-cells from the same patients as the recognized tumors. Its lack of MHC restriction circumvents the severe restriction that matching MHC types imposes on the utility of classical T-cell recognition where therapy with such T-cells must be done only in MHC-appropriate patients. Our studies have shown that introduction of the genes which encode this TCR into any third-party peripheral blood lymphocyte confers the same MHC-unrestricted tumor recognition, showing that this reactivity is clearly TCR mediated. Furthermore, the recognition of tumors is markedly enhanced by exposure of the target cell to TNF-related apoptosis inducing ligand (TRAIL), a molecule with significant tumor specificity, also being explored as a novel reagent in cancer trials. Current efforts are attempting to define what other molecules besides TRAIL participate in this recognition and define the target antigen. Recent developments show that the recognition entity is completely unprecedented and may represent a new type of immunological recognition by a T-cell. In parallel with this scientific investigation, we are proceeding with the optimization of the native TCR which confers tumor recognition. Mutations of the normal antigen binding regions of the TCR has led to greatly improved tumor recognition without evidence for new "off target" reactivity. We have been able to use genetic engineering to introduce these improved TCRs into the immune cells of any RCC patient and show they can now recognize and react with most renal cancers. We now know the structure on the kidney cancer that is being attacked and it is not like any other immune cell target recognized by a standard TCR. It appears to be the TRAIL molecule bound to one of its normal receptors and there is no MHC like molecule involved. Finally, using clues from the nature of the recognition structure and the native TCR, we are trying to determine the frequency of such reactivity in normal subjects and patients with cancer. This may better determine the potential role of such cells in tumor control and rejection. We have also begun an experimental protocol with this receptor giving genetically constructed cells to patients who have exhausted standard therapies for metastatic renal cancer to see if we can see regression of their tumors.